Abstract
Disruption of circadian regulation was recently shown to cause diabetes and metabolic disease. We have previously demonstrated that retinal lipid metabolism contributed to the development of diabetic retinopathy. The goal of this study was to determine the effect of diabetes on circadian regulation of clock genes and lipid metabolism genes in the retina and retinal endothelial cells (REC). Diabetes had a pronounced inhibitory effect on the negative clock arm with lower amplitude of the period (per) 1 in the retina; lower amplitude and a phase shift of per2 in the liver; and a loss of cryptochrome (cry) 2 rhythmic pattern in suprachiasmatic nucleus (SCN). The positive clock arm was increased by diabetes with higher amplitude of circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl-hydrocarbon receptor nuclear translocator-like 1 (bmal1) and phase shift in bmal1 rhythmic oscillations in the retina; and higher bmal1 amplitude in the SCN. Peroxisome proliferator-activated receptor (PPAR) α exhibited rhythmic oscillation in retina and liver; PPARγ had lower amplitude in diabetic liver; sterol regulatory element-binding protein (srebp) 1c had higher amplitude in the retina but lower in the liver in STZ- induced diabetic animals. Both of Elongase (Elovl) 2 and Elovl4 had a rhythmic oscillation pattern in the control retina. Diabetic retinas lost Elovl4 rhythmic oscillation and had lower amplitude of Elovl2 oscillations. In line with the in vivo data, circadian expression levels of CLOCK, bmal1 and srebp1c had higher amplitude in rat REC (rREC) isolated from diabetic rats compared with control rats, while PPARγ and Elovl2 had lower amplitude in diabetic rREC. In conclusion, diabetes causes dysregulation of circadian expression of clock genes and the genes controlling lipid metabolism in the retina with potential implications for the development of diabetic retinopathy.
Highlights
The circadian clock is comprised of transcriptional/translational feedback loops of clock genes
Periodicity analysis by COSOPT demonstrated that expression levels of all examined clock genes (CLOCK, bmal1, per1, per2, cry1 and cry2) in livers isolated from both control and diabetic rats had a rhythmic oscillation pattern (Table 2)
In mammals circadian timing system includes the central master circadian pacemaker located in the suprachiasmatic nucleus (SCN) and peripheral oscillators distributed throughout the body [2]
Summary
The circadian clock is comprised of transcriptional/translational feedback loops of clock genes. In the mammalian circadian clock system, SCN is a ‘‘master’’ clock, with a series of ‘‘peripheral’’ clocks that are located in almost all the peripheral tissues [2]. The physiological rhythmicity in peripheral tissues is mainly controlled by local molecular clock with the SCN functioning as a synchronizer of peripheral oscillators [3]. Light is the main synchronizer (Zeitgeber) of central circadian rhythmicity, various signals associated with food intake (or fasting) are potent synchronizers for secondary clocks in peripheral organs such as liver, which plays critical role in the development of metabolic syndrome/type 2 diabetes [4]. 10% of the genes exhibit circadian expression in the liver, indicating that circadian rhythmicity is important for hepatic physiology [5,6]
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